The discovery of the human major histocompatibility complex (hereinafter "MHC") dates from the mid-1950's, when leukoagglutinating antibodies were first found in the sera of multiply transfused patients in a pattern that suggested the antisera were detecting alloantigens, antigens present on the cells of some individuals of a given species which are products of a polymorphic genetic locus. The role of these antigens in determining the success of tissue and organ transplants was soon appreciated and provided the initial studies of genes that determine human leukocyte antigens (hereinafter "HLA").
The HLA system is extremely polymorphic, having multiple different alleles at each known genetic locus. Based on their tissue distribution and structure, HLA antigens have been divided into two broad classes: Class I antigens which include the HLA-A, -B, and -C antigens found on virtually every human cell and which have counterparts in other mammalian cells including the murine system; and Class II antigens including the HLD-, DR, DQ, and DP antigens found chiefly on the surfaces of immunocompetent cells including macrophages/monocytes, activated T-lymphocytes, and B lymphocytes. Class II antigens also have counterparts in other mammalian systems such as murine mammals. The presence of these Class I and Class II antigenic molecules plays a major role in the functional heterogeneity of peripheral T-cells.
The different regulatory and effector functions of T-cells are mediated by different subpopulations of cells which can be distinguished by differences in their phenotypes and antigenic determinants (identifiable by different monoclonal antibodies). This has led to the typing of T cell functional subsets in accordance with the expression of specific surface molecules which are commonly designated by the letter "T" followed by a number. Based on functional differences between T4 and T8 cells, the peripheral blood T-cells can be broadly divided into two populations: one population constituting approximately 65% of peripheral blood T-cells is T4.sup.+ ; the other constituting approximately 35% of all peripheral blood T-cells is T8.sup.+. The T8.sup.+ cell may be activated to become a cytolytic T lymphocyte (hereinafter "CTL cell") which functions as a cytotoxic effector cell and plays an important role in the hosts' defense against foreign bodies. In combination with natural killer cells (hereinafter "NK cells") and lymphokine activated killer cells (hereinafter "LAK cells"), these cells respond to protect the body against invasion by foreign cells and substances. The role of the T4.sup.+ cell has been traditionally viewed as an inducer cell for the activation of other T-cell subpopulations. This role is achieved in combination with an accessory cell or antigen presenting cell (hereinafter "APC") which bears Class II MHC molecules on its surface and is able to take up and process an identifiable antigen. The antigen presented by an APC bearing Class II molecules activates specific T4.sup.+ cells. The activated T4.sup.+ cells in turn secrete a variety of lymphokines to initiate the effector and cytolytic functions of other T-cell lymphocytes. It is noteworthy that with the increasing use of lymphocyte-mediated immunotherapies including those directed against tumors, all such immunotherapies utilize only those activated lymphocytes equipped with cytolytic effector function such as CTL cells, NK cells, and LAK cells. T-cells of the inducer phenotype are traditionally viewed as lacking the necessary cytolytic activity and therefore have not been considered useful for treatment of tumors as immunotherapeutic lymphocytes.
The human system of multiple T-cell subpopulations has a direct counterpart in the murine system. There are two major functional subsets of T-lymphocytes in the murine system [Cantor and Boyse, J. Exp. Med. 141:1376 (1975)]. The L3T4.sup.+ subset of T-lymphocytes has inducer or helper functions and is generally activated by APCs that bear exogenous antigen and express Class II molecules (Ia) of the MHC [Dialynas et al., Immunol. Rev. 74:29 (1983)]. This subset is equivalent to the T4.sup.+ lymphocyte subpopulation in humans. The second major T-cell subset expresses Lyt-2 determinants and possesses either suppressor or cytolytic functions. These are equivalent to T8.sup.+ lymphocytes in humans. When activated, Lyt-2 cells become cytolytic T-lymphocytes (CTL cells) which generally lack the L3T4.sup.+ antigenic marker and which recognize Class I molecules of the MHC [Zinkernagel and Doherty, J. Exp. Med. 141:1427 (1975)].
As in the human system, it has been traditionally viewed that L3T4.sup.+ inducer T cells help initiate the effector functions of other T-lymphocytes, but do not demonstrate any cytolytic effect themselves. Very recently however, several investigators observed an effector function for selected L3T4.sup.+, antigen-specific, Ia-restricted T-cell clones [Tites et al., J. Immunol. 135:25 (1985); Nakamura et al., J. Immunol. 136:44-47 (1986); Lukacher et al., J. Exp. Med. 162:171 (1985)]. These investigations comprised in-vitro experiments in which selected L3T4.sup.+ clones appeared to be cytolytic in short-term (less than 6 hours) chromium release assays for Ia-bearing B-cell hybridoma targets in the presence of antigen. The primary thrust of each report dealt with the specificity and the killing mechanism(s) for the observed cytotoxicity. To date, therefore, there is little knowledge or appreciation as to: whether inducer T-cells generally in murine and human systems are able to express cytolytic effector function; whether all major types of antigen presenting cells are sensitive to such cytolytic activity; whether such cytolytic activity can be maximally expressed and, if so, under what conditions; and whether such inducer T-cell cytolytic activity can be utilized in-vivo for any therapeutic purpose.